Parkinson's disease (PD) is a common late onset, progressive neurodegenerative disease characterized by degeneration of subcortical neuronal populations, including dopaminergic neurons of substantia nigra, pars compacta (SNpc), and presence of the cytoplasmic inclusions composed of alpha-synuclein. While the causes of PD are not known, genetic and biochemical abnormalities of alpha-synuclein are directly implicated in the pathogenesis of PD and other alpha-synucleinopathies. Causal link between alpha-synuclein abnormalities and neurodegeneration is shown by various genetic models where alpha-synuclein abnormalities lead to adult- onset neurological disease with neurodegeneration. Some models exhibit many of the features of human alpha-synucleinopathies, including aberrant aggregation of alpha-synuclein and neurodegeneration in subcortical regions. Our studies indicate that alpha-synucleinopathy in tg mice is associated with oxidative stress and mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of PD and other a-synucleinopathies, we will examine the pathological relationships between mitochondrial dysfunction, oxidative stress and alpha-synucleinopathies in Hua-Syn Tg mice and in cell models (Aims 1 and 2). In addition, our studies show that alpha-synuclein transgenic mice exhibit increased vulnerability to neurodegeneration induced by the chronic MPTP treatment. Thus, there could be a direct pathologic link between alpha-synuclein, mitochondrial dysfunction via environmental agents (such as pesticides), and neurodegeneration. We will use pesticides that are known to inhibit complex I activity to define the pathological interactions between these factors that known risk factors for PD using cell culture (Aim 3) and transgenic mouse models (Aim 4). These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related alpha-synucleinopathies are fatal neurodegenerative diseases affecting ~1,000,000 individuals annually in US. Studies indicate that PD is associated with alpha-synuclein abnormalities, mitochondrial dysfunction, and pesticide exposure. We will determine how intrinsic (alpha- synuclein) and extrinsic (environmental toxins) factors act in concert of pathologically affect mitochondrial function and lead to neurodegeneration. Our finding will lead to better understanding of PD and new targets for therapeutic intervention.